Mature microRNAs (miRNA) are small, noncoding RNAs that post-transcriptionally regulate gene expression. Though miRNAs are essential for many fundamental cell processes, the mechanisms regulating miRNA biogenesis are poorly understood. miRNA biogenesis is a multi-step process in which long, genetically-encoded primary miRNAs are cleaved into precursor and then mature miRNAs. Each step is important for mature miRNA expression, and thus represents targets for regulation or therapeutics. I propose to study the control mechanisms for miRNA biogenesis in general and let-7 in particular in a genetically rich host - C. elegans. Let-7 is an important tumorigenesis regulator that is conserved across phyla. Though proper let-7 levels are crucial for appropriate cell growth, the fundamental mechanisms underlying let-7 expression specifically and miRNA biogenesis in general are not well understood. I have identified a new function for the period protein homolog LIN-42 in post-transcriptionally regulating let-7 biogenesis by a novel mechanism. My studies will determine if LIN-42 globally regulates mature miRNA production, and elucidate the mechanism whereby LIN-42 performs this novel and important function. Ultimately, these studies will increase our understanding of the development and microRNA biogenesis pathways, and may illuminate a novel function of period proteins and important links between microRNA biogenesis regulation, biological timing mechanisms and tumorigenesis. Public Health Relevance: microRNAs are essential for many fundamental cell processes, and misregulation of miRNA expression often results in tumorigenesis. Unraveling the mechanisms controlling miRNA biogenesis will provide insight into the fundamental processes regulating tumorigenesis while highlighting pathways containing novel targets for cancer therapy and prevention.